CN101453982B - Two-piece, internal-channel osmotic delivery system flow modulator - Google Patents

Abstract

An osmotic delivery system flow modulator includes an outer shell constructed and arranged for positioning in an opening of a reservoir of an osmotic delivery system, an inner core inserted in the outer shell, and a fluid channel having a spiral shape defined between the outer shell and the inner core. The fluid channel is adapted for delivery of an active agent formulation from the reservoir of the osmotic delivery system.

Description

Two-piece, internal-channel osmotic delivery system flow modulator

The cross reference of related application

The application requires the priority of the U.S. Provisional Application 60/809,451 on May 30th, 2006, and the content of described application is merged in this paper as a reference.

Background of invention

Relate generally to of the present invention is used for continuing at fluid environment the osmotic delivery system of active agent delivery.More specifically, the present invention relates to be used at the flow conditioner of fluid environment from the osmotic delivery system active agent delivery.

Fig. 1 has illustrated the osmotic delivery system 40 of prior art, and is described as people's such as Peterson United States Patent (USP) 6,524,305.Described delivery system 40 comprises the housing 42 that holds penetrating agent 47 and activating agent 44.Resolution element 46 forms spacer between penetrating agent 47 and activating agent 44.Semi-permeable plug 48 is inserted in first opening 45 of housing 42.Semi-permeable plug 48 optionally allows fluid to enter the inside of housing 42.Flow conditioner 20 is inserted in second opening 39 of housing 42.Flow conditioner 20 allows activating agent 44 to leave the inside of housing 42, and controls the inside of fluid back-diffusion to housing 42.When osmotic delivery system 40 is placed in the fluid environment, enter housing 42 and infiltrate penetrating agent 47 by semipermeable plug 48 from the fluid of housing 42 outsides, cause that penetrating agent 47 expands.Penetrating agent 47 moves resolution element 46 when expanding, and causes that activating agent 44 is delivered to applied environment by flow conditioner 20.

In the osmotic delivery system 40 of the prior art shown in Fig. 1, the outer surface of flow conditioner 20 comprises spiral helicine delivery path 32, activating agent 44 by described delivery path 32 from the internal circulation of housing 42 to the outside.Form the inner surface 43 of screw thread (thread) the 36 butt housings 42 of helical delivery path 32, make activating agent 44 by helical delivery path 32 time, contact the inner surface 43 of housing 42.Spacing, distance, cross-sectional area and shape to helical delivery path 32 are selected, and make that from the fluid environment to the housing back-diffusion in 42 minimizes.Filler opening 22 and steam vent 24 are provided in flow conditioner 20.When this osmotic delivery system 40 of assembling, at first flow conditioner 20 is inserted in the housing 42.By filler opening 22 activating agent 44 is expelled in the housing 42 then, and the gas in the housing 42 flows out by steam vent 24., end cap 26 be inserted in hole 22,24, make and only sending of activating agent 44 taken place by helical delivery path 32 thereafter.

From foregoing as seen, still wish the reliability and the flow adjustment ability that in osmotic delivery system, provide other.

Summary of the invention

In one aspect, the present invention relates to the osmotic delivery system flow conditioner, it comprises the shell that is configured and arranges the vessel port that is used for being positioned at osmotic delivery system, be inserted into the inner core in the shell, and the helical form flow channel that between described shell and inner core, limits, described flow channel is suitable for the container delivery of active agent formulation from osmotic delivery system.

In one aspect of the method, the present invention relates to osmotic delivery system, it comprises container; Be arranged on first end of described container, the mobile semipermeable plug that is used for optionally allowing to enter container; Be arranged on the flow conditioner of second end of described container, described flow conditioner comprises and is suitable for being delivered to internal helicoid passage in the fluid environment that described osmotic delivery system works therein with being included in active agent formulation in the container.

In a further aspect, the present invention relates to be used for the implantable delivery system of active agent formulation, it comprises the container of being made by non-permeable material, first Room that comprises the osmotic engine material in described container, second Room that comprises active agent formulation in described container, be arranged on container first terminal and the first Room adjacency semipermeable plug and be arranged on second Room of container and the aforesaid flow conditioner of the second Room adjacency.

From the following description book and the apparent other features and advantages of the present invention of claim subsequently.

Description of drawings

Description of drawings as described below typical embodiment of the present invention, and it should be thought of as and limit the scope of the invention, because the present invention can allow other same effectively embodiment.Not necessarily pro rata in the accompanying drawing, and for clarity and conciseness, some feature among the figure and some view may amplify on ratio or schematically.

Fig. 1 describes the cutaway view of prior art osmotic delivery system.

Fig. 2 A describes the phantom of flow conditioner, and described flow conditioner has inner core that is inserted in the shell and the internal helicoid flow channel that is formed in the inner core.

Fig. 2 B describes the phantom of flow conditioner, and described flow conditioner has inner core that is inserted in the shell and the internal helicoid flow channel that is formed in the shell.

Fig. 2 C describes the phantom of flow conditioner, and described flow conditioner has inner core that is inserted in the shell and the internal helicoid flow channel that is formed in inner core and the shell.

Fig. 2 D describes the phantom of flow conditioner, and described flow conditioner has inner core and the mobile insert that is inserted in the shell, and described mobile insert comprises the internal helicoid flow channel that is inserted between inner core and the shell.

Fig. 2 E describes the phantom of flow conditioner, and described flow conditioner has the inner core that is inserted in the shell and the composition surface on inner core and the shell, is used to prevent that inner core from discharging from shell.

Fig. 3 describes the cutaway view of the osmotic delivery system of the flow conditioner with Fig. 2 A.

The external accumulative total that Fig. 4 describes the activating agent that the osmotic delivery system of using Fig. 3 obtains discharges.

Detailed Description Of The Invention

With reference now to writing up the present invention as the several preferred embodiments that illustrate in the accompanying drawing.When describing preferred embodiment, set forth many details and fully understood of the present invention so that provide.Yet those skilled in the art can put into practice the present invention under the situation of not using some or all these details.In other situation, well-known features and/or processing step are not described in detail, so that unnecessarily make the present invention unclear.In addition, similar or identical reference number is used to represent shared or similar elements.

Fig. 2 A describes the phantom be used for from the flow conditioner 200 of the container delivery of active agent formulation of osmotic delivery system to 2E.With reference to figure 2A, flow conditioner 200 has the entrance side 201 of the active agent formulation in the container that is exposed to osmotic delivery system and is exposed to the outlet side 203 of the fluid environment that osmotic delivery system works therein.Typically, fluid environment is a liquid phase environment, that is to say, described fluid comprises water.Flow conditioner 200 comprises shell 202 and is inserted in the shell 202 and is generally columniform inner core 204.Between shell 202 and inner core 204, there is spiral helicine flow channel 206 to extend to outlet side 203 from the entrance side of flow conditioner 200.All of flow channel 206 or significant part can be helical form.Flow channel 206 is in flow conditioner 200 inside.Therefore, flow conditioner 200 forms barrier between the container of active agent formulation by flow channel 206 and osmotic delivery system.

In Fig. 2 A-2C, the outer surface 210 of inner core 204 cooperates with the inner surface 212 of shell 202.Flow channel 206 can be formed in the outer surface 210 of inner core 204, and shown in Fig. 2 A, perhaps flow channel 206 is formed in the inner surface 212 of shell 202, shown in Fig. 2 B.Perhaps, shown in Fig. 2 C, fluid passage 206 can comprise the first flow channel 206a in the outer surface 210 that is formed on inner core 204 and be formed on the second flow channel 206b in the inner surface 212 of shell 202, and wherein the first flow channel 206a and the second flow channel 206b are against each other or be communicated with.All of each flow channel 206a, 206b or significant part are helical form.Perhaps, shown in Fig. 2 D, the insert 214 that flows can be arranged between the inner surface 212 of the outer surface 210 of inner core 204 and shell 202, and the insert 214 that wherein flows provides flow channel 206.The insert 214 that flows can be for example coil pipe, and the distance between each circle of pipe plays the effect of flow channel 206.Perhaps, the insert 214 that flows can be the cylinder or the sleeve pipe of the hollow that wherein is formed with helical groove, and wherein helical groove plays the effect of flow channel 206.Flow channel 206 can have any required cross section, and the example comprises annular or D shape.The flow channel of in Fig. 2 A-2E, having represented D shape.The length of flow channel 206 depends on the structure of osmotic delivery system and required rate of release.Typically, ((spiral) length of flow channel 206 is 10 to 50mm.Typically, the effective cross-section diameter of flow channel 206 is 0.1 to 0.5mm.These scopes provide as an example, rather than are used to limit the present invention, except as otherwise noted.

With reference to figure 2A-2D, the maximum outside diameter of inner core 204 and the maximum inner diameter of shell 202 are selected, make between the inner surface 212 of the outer surface 210 of inner core 204 and shell 202, to form interference fit or sealing.This interference fit or sealing restriction preparation flow in the passage 206.This interference fit or sealing are enough to prevent that inner core 204 and/or mobile insert 214 are from shell 202 discharges.On the other hand, in Fig. 2 A-2C, the mating part on the surface 210,212 of inner core 204 and shell 202 can for example comprise respectively and be threaded, bonding connection, feature such as be welded to connect, so that in addition with respect to the fixing inner core 204 of shell 202.In Fig. 2 D, can between the part of interior and outer surface 214a, the 214b of the mobile insert 214 that cooperates with the surface 210,212 of inner core 204 and shell 202 respectively, form similar connection features.Fig. 2 E discloses the alternative approach that is used to prevent that inner core 204 from discharging from shell 202, and it is included in the outside shoulder 216 on the outer surface 210 of inner core 204, the inboard shoulder 218 butt/engagements on the inner surface 212 of itself and shell 202.Outlet side 203 discharges of inner core 204 have been prevented like this by flow conditioner 200.Butt/the mating surface of shoulder 216,218 can be flat or can be and phases down, as shown in Fig. 2 E.

Using butt/engagement shoulder 216,218 to prevent that inner core 204 is discharged to the fluid environment that osmotic delivery system works therein from shell 202 goes among the arbitrary embodiment shown in Fig. 2 A-2D.In addition, any feature of embodiment shown in Fig. 2 A-2E can be exchanged and combination, to produce the alternate embodiment of flow conditioner 200.For example, in Fig. 2 E, spiral helicine passage also can be arranged in the inner surface 212 of shell 202 as shown in Fig. 2 C.Perhaps, in Fig. 2 D, spiral helicine passage also can be arranged in the inner surface 212 of shell 202 and/or the outer surface 210 of inner core 204, respectively described in Fig. 2 A and 2B, wherein the flow channel 206 in the passage in shell 202 and/or the inner core 204 and the mobile insert 214 in abutting connection with or be communicated with.

With reference to figure 2A-2E, shell 202, inner core 204 and mobile insert 214 are preferably formed by inertia and biocompatible material.The example of inert biocompatible material includes but not limited to non-reactive polymer and metal for example titanium, rustless steel, platinum and their alloy and cochrome.When can be used for wherein wishing in active agent formulation being delivered to the fluid environment that osmotic delivery system works therein, non-reactive polymer avoids the interactional situation between active agent formulation and the metal material.The example of the non-reactive polymer that is fit to includes but not limited to PAEK for example polyether-ether-ketone and polyaryletheretherketone, ultra-high molecular weight polyethylene, fluorizated ethylene-propylene, polymethylpentene and liquid crystal polymer.Preferably, at least following surface is not by making or scribble described material to the material that active agent formulation has an illeffects, and described surface is included in the surface of the shell 202, inner core 204 and the mobile insert 214 that are exposed to active agent formulation when active agent formulation flows through flow channel 206.In a preferred embodiment, above-mentioned surface is made by inert and biocompatible nonmetallic materials.This nonmetallic materials can be non-reactive polymer, and the example provides above-mentioned.

Can select length, shape of cross section and the circulating area of flow channel 206, make the average linear velocity of active agent formulation by flow channel 206 than material because diffusion or infiltration are higher from the linear average linear velocity that inwardly flows into of fluid environment that osmotic delivery system works therein.Can have decay like this or relax the effect of back-diffusion,, then may pollute the active agent formulation in the osmotic delivery system if describedly back-diffusion is not controlled.Can regulate the rate of release of active agent formulation by the geometry of regulating flow channel 206, as described below.

The convective flow of activating agent by flow channel 206 is by the surfactant concentration decision in the active agent formulation in the container of the pump rate of osmotic delivery system and osmotic delivery system.Convective flow can be expressed as:

Qca＝(Q)(Ca) (1)

Wherein Qca is the convective transport that is expressed as mg/ days activating agent (beneficial), and Q is expressed as cm ³The overall convective transport and the Ca of the active agent formulation in/sky are expressed as mg/cm ³The container of osmotic delivery system in active agent formulation in the concentration of activating agent.

The diffusional flow that activating agent leaves flow channel 206 is surfactant concentration and the shape of cross section of diffusibility and flow channel 206 and the function of length.Diffusional flow can be expressed as:

$Q_{\mathrm{da}}=\frac{\mathrm{D\π}{r}^2\mathrm{\Δ}{C}_a}{L}---\left(2\right)$

Wherein Qda is the diffusion transhipment that is expressed as mg/ days activating agent, and D is expressed as cm ²The diffusibility of passing through flow channel 206 in/sky, r is the effective internal diameter that is expressed as the flow channel 206 of cm, Δ Ca is expressed as mg/cm ³The osmotic delivery system container in the surfactant concentration of active agent formulation and the surfactant concentration in the fluid environment in delivery orifice 205 outsides of flow conditioner 200 poor, and L is (spiral) length that is expressed as the flow channel 206 of cm.

Usually, the surfactant concentration in the osmotic delivery system in the active agent formulation is more much bigger than the surfactant concentration in the fluid environment of using, and makes that described poor Δ Ca can be near the surfactant concentration Ca in the active agent formulation in the osmotic delivery system.Therefore:

$Q_{\mathrm{da}}=\frac{\mathrm{D\π}{r}^2{C}_a}{L}---\left(3\right)$

Usually the convective flow of the diffusion flux specific activity agent of expectation maintenance activating agent is much smaller.This can be expressed as follows:

$\frac{Q_{\mathrm{da}}}{Q_{\mathrm{ca}}}=\frac{\mathrm{D\&pi;}{r}^2{C}_a}{Q{C}_{a}L}=\frac{\mathrm{D\&pi;}{r}^2}{\mathrm{QL}}<1---\left(4\right)$

Equation (4) expression relative diffusion flux reduces with the increase of volume flow velocity and path-length, increases with the increase of diffusibility and channel radius, and irrelevant with surfactant concentration.

Wherein flow channel 206 is can approximate representation as follows at the diffusion flux of the water at osmotic delivery system split shed place:

$Q_{\mathrm{wd}}\left(\mathrm{res}\right)=C_{o}Q{e}^{(-\mathrm{QL}/D_{w}A)}---\left(5\right)$

Wherein Co is expressed as mg/cm ³The CONCENTRATION DISTRIBUTION of water, Q is expressed as mg/ days mass velocity, L is the length that is expressed as the flow channel 206 of cm, Dw is expressed as cm ²The water in/sky is expressed as cm by the diffusibility and the A of material in the flow channel 206 ²The cross-sectional area of flow channel 206.

The fluid dynamic pressure drop of crossing over delivery orifice can be calculated as follows:

$\mathrm{\&Delta;P}=\frac{8\mathrm{QL\&mu;}}{{\mathrm{\&pi;r}}^4}---\left(6\right)$

Wherein Q is expressed as mg/ days mass velocity, and L is the helical flow passage length that is expressed as cm, and μ is the viscosity of preparation, and r is the effective internal diameter that is expressed as the flow channel of cm.

Fig. 3 represents to comprise the osmotic delivery system 300 of flow conditioner 200.Although osmotic delivery system 300 is expressed as the flow conditioner 200 with Fig. 2 A, apparent, any flow conditioner 200 shown in Fig. 2 A-2E can be used for osmotic delivery system 300.Osmotic delivery system 300 comprises container 302, and its size can be and makes and it can be implanted in vivo.Container 302 has open end 304,306.Flow conditioner 200 is inserted in the open end 304.Semipermeable plug 308 is inserted in the open end 306.

Semipermeable plug 308 is fluid flow films in the container 302 of the fluid environment that works therein from osmotic delivery system of control.Semipermeable plug 308 allows to enter container 302 from the fluid of fluid environment.Because the semipermeability character of semipermeable plug 308 is prevented from by semipermeable plug 308 flow containers 302 compositions in the container 302.Semipermeable plug 308 can partially or completely be inserted in the open end 306.In the previous case, semipermeable plug 308 can comprise the end portion 308a of expansion, and it works as the stopping element that the end with container 302 meshes.The outer surface 308b of semipermeable plug 308 can have projection or the burr 308c with inner surface 310 engagement of container 302, thereby is locked in semipermeable plug 308 on the container 302 and allows to form sealing between container 302 and semipermeable plug 308.Container 302 can also comprise undercutting, is used to accept the projection 308c on the semipermeable plug 308.The semipermeable materials that is used for semipermeable plug 308 is the material that can meet the shape of container 302 and can adhere to the inner surface 310 of container 302 when moistening.Typically, these materials are polymeric materials, and it can require to select according to pump rate and system configuration.The example of the semipermeable materials that is fit to includes but not limited to for example for example polyurethane and polyamide, polyphenylene ether-polyamide copolymer, thermoplastic copolyester or the like of hydroxyethyl meth acrylate (HEMA) and elastomeric material of plastifying cellulosic material, enhanced polymethyl methacrylate (PMMA).Common optimization polyurethane.

In container 302, limit two chambers 312,314.Piston that is for example slided by spacer 316 in chamber 312,314 or flexible membrane are separated, and described spacer is configured to cooperate container 302 in and produces sealing and contact and be used in container 302 longitudinally mobile or be out of shape.Preferably, spacer 316 is formed by the elastomeric material of impermeability.For example, spacer 316 can and can comprise the annular projection 316a that forms sealing with the inner surface 310 of container 302 for the sliding plunger made by the impermeability elastomeric material.Osmotic engine material 318 is arranged in the chamber 314 with semipermeable plug 308 adjacency, and active agent formulation is arranged in the chamber 312 with flow conditioner 200 adjacency.Spacer 316 makes active agent formulation 320 and the environment liquid separation that is allowed to enter by semipermeable plug 308 container 302, make in use, when steady-flow, active agent formulation 320 is to be discharged from by flow channel 206 by the suitable speed of the speed of semipermeable plug 308 inflow containers 302 from fluid environment with fluid.

Osmotic engine material 318 can be as directed tablet form.Can use one or more this tablets.Perhaps, osmotic engine material 318 can have other shape, quality, density and denseness.For example, osmotic engine material 318 can be powder or particle form.Osmotic engine material 318 can comprise osmopolymer (osmopolymer).Osmopolymer is to absorb aqueous fluid for example water and biological fluid and expand when sucking aqueous fluid or be expanded to poised state and keep signal portion and be absorbed fluidic hydrophilic polymer.Osmopolymers swell or be expanded to very high degree, being usually expressed as 2 to 50 times of volumes increases.Osmopolymer is can yes or no crosslinked.Preferred osmopolymer is slight cross-linked hydrophilic polymer, this crosslinked be by covalent bond or ionic bond or the residual crystal region after expanding forms.Osmopolymer can be plant, animal or synthetic source.Be suitable for the osmopolymer of osmotic engine material 318 or the example of hydrophilic polymer and include but not limited to that molecular weight is 30,000 to 5,000,000 poly-(hydroxy alkyl methacrylate); Molecular weight is 10,000 to 360,000 polyvinylpyrrolidone (PVP); Anionic and cationic hydrogel; Compound polyelectrolyte; The low acetate root is residual, be 200 to 30,000 polyvinyl alcohol with Biformyl, formaldehyde or glutaraldehyde cross-linking and the degree of polymerization, methylcellulose, crosslinked agar and the mixture of carboxymethyl cellulose; The mixture of hydroxypropyl emthylcellulose and sodium carboxymethyl cellulose; The mixture of Cellulose ethyl hydroxypropyl ether and sanlose; Sodium carboxymethyl cellulose; Carboxymethyl-cellulose potassium salt; By water-fast, the expandable copolymer of water that the dispersion of the finely divided copolymer of maleic anhydride and styrene, ethylene, propylene, butylene or isobutene. forms, every mole of maleic anhydride of every kind of copolymer has 0.001 to about 0.5 mole saturated cross-linking agent; The water swellable polymer of N-vinyl lactam; Polyethylene glycol oxide-polypropylene oxide gel; Polyoxybutylene-polyethylene block copolymer gel; Tragon; Carbopol gel; Polyester gel; Polyurea gel; The polyethers gel; Polyamide gels; Poly-cellulose gel; Poly-gummy gel (polygumgel); Absorb and the glassy hydrogel of adsorption and permeation and reduce the initial exsiccant hydrogel of the water of its vitrification point.Other example of osmopolymer comprises the polymer that forms hydrogel, for example: CARBOPOL

, tart carboxyl polymer, a kind of polymerizing acrylic acid thing and crosslinked with polyene propyl group sucrose has another name called polyacrylic acid and carbopol, and molecular weight is 250,000 to 4,000,000; CYNAMER Polyacrylamide; The expandable indenes of crosslinked water-maleic anhydride polymer; Molecular weight is 80,000 to 200,000 GOOD-RITE

Polyacrylic acid; Molecular weight is 100,000 to 5,000,000 and more high-molecular weight POLYOX

Polyethylene oxide polymer; Starch graft copolymer; The AQUA KEEPS that forms by the glucose unit of condensation Acrylate polymer polysaccharide, for example crosslinked polysaccharide (polygluran) of diester; Or the like.Except osmopolymer or replace osmopolymer, osmotic engine material 318 can also comprise penetrating agent (osmagent).Penetrating agent comprises the inorganic and organic compound that shows the osmotic pressure gradient of striding semipermeable wall with respect to external fluid.Osmagents imbibe fluid in osmosis system, thereby utilize fluid to promote preparation, be used to send and pass through flow conditioner.Penetrating agent has another name called osmotically active chemical compound or solute.The example that can be used for the penetrating agent of osmotic engine material 318 comprises magnesium sulfate, magnesium chloride, sodium chloride, potassium sulfate, sodium sulfate, lithium sulfate, potassium hydrogen phosphate, mannitol, carbamide, inositol, Magnesium succinate, tartaric acid, carbohydrate for example cottonseed sugar (raffmose), sucrose, glucose, lactose, sorbitol and composition thereof.

Active agent formulation 320 can comprise one or more activating agents. activating agent can be the material of any physiology or pharmacological activity, particularly becomes known for being delivered to those of human body or animal body, for example medicine, vitamin, nutrient etc.Can include but not limited to act on infectious disease by the activating agent that flow conditioner 200 usefulness osmotic delivery system 300 are sent, chronic pain, diabetes, peripheral nervous, adrenoreceptor, cholinoceptor, skeletal muscle, cardiovascular system, smooth muscle, blood circulation, the synapse position, the neural effector bonding station, endocrine and hormone system, immune system, reproductive system, skeletal system, autocrine system, digestion and Excretory system, histamine system and central nervous system.The reagent that is fit to can be selected from for example synthetic analogues of protein, enzyme, hormone, polynucleotide, nucleoprotein, polysaccharide, glycoprotein, lipoprotein, polypeptide, steroidal, analgesic, local anesthetic, antibiotic, antiinflammatory usefulness corticosteroid, eye medicinal and these materials.Preferred activating agent comprises macromole (protein and peptide) and highly effective activating agent.Activating agent can be used as number of chemical and physical form exists, for example solid, liquid and slurry.Except one or more activating agents, preparation 320 can randomly comprise pharmaceutically acceptable carrier and/or other composition, for example antioxidant, stabilizing agent, buffer agent and penetration enhancers.

The material that is used for container 302 should be fully hard, do not change its size or shape so that stand the expansion of osmotic engine material 318.In addition, described material should guarantee under can be in the implantation process not suffered stress of container 302 or owing to seepage, crack under the stress of the pressure that produces in the operating process, break or be out of shape.Container 302 can be formed by inert, biocompatible, natural or synthetic material known in the art.The material of container 302 can be or not be biological erodible.Biological erodible material is partly dissolved at least, degrades in the fluid environment of its application or otherwise corrosion.Preferably, the material of container 302 is not biological erodible.Usually, the material of preferred container 302 is to be applicable to human those that implant.Preferably, the material right and wrong of container 302 are infiltrative, and particularly the preparation stability in container 302 is to the fluid environment of using when responsive.The example that is suitable for the material of container 302 comprises non-reactive polymer or biocompatible metals or alloy.The example that is used for the non-reactive polymer of container 302 includes but not limited to for example acrylonitrile-butadiene-styrene terpolymer of acrylonitrile polymer; Halogenated polymer is politef, polychlorotrifluoroethylene, tetrafluoroethene and hexafluoropropylene copolymer for example; Polyimides; Polysulfones; Merlon; Polyethylene; Polypropylene; Polrvinyl chloride-acrylic copolymer; Merlon-acrylonitrile-butadiene-styrene (ABS); And polystyrene.The example of the metallic alloy of container includes but not limited to rustless steel, titanium, platinum, tantalum, gold and their alloy, and the rustless steel of gold-plated ferroalloy, platinized ferroalloy, cochrome and titanium nitride coating.Use and wherein chemosensitive application in the body of preparation to implantation position for the decisive application of size, high payload capability, long duration, preferred container 302 is by titanium or have greater than the titanium alloy of 60% (usually greater than 85%) titanium and make.

Can select the diameter of flow conditioner 200, make flow conditioner 200 can be press fit in the open end 304 of container 302.Also might on the inner surface 310 of the outer surface 220 of shell 202 and container 302, comprise for example screw thread of feature, be used for respect to the fixing flow conditioner 200 of container 302.

Following examples are used to illustrate the present invention, should not be seen as restriction the present invention, unless explanation is arranged herein in addition.

Be used for the treatment of for example following assembled of osmotic delivery system of the interferon-ω of hepatitis C (IFN-ω) illustrated in fig. 3 comprising: (i) make and have at its end the container of undercutting by implanting the level titanium alloy, the osmotic engine material that (ii) comprises two cylindrical tablet, each tablet mainly comprises the sodium chloride salt with cellulose and polyvidone binding agent, (iii) piston, (iv) make and have the semipermeable plug of the maintenance burr that cooperates with undercutting in the container by polyurethane, (the flow conditioner that v) has the spiral type inner flow passage of D shape cross section, diameter 0.25mm, helix length is 35mm and the (suspension preparation that vi) comprises the granular preparation that is suspended in the IFN-ω in the non-water vehicle.

Suspension preparation with the vessel filling 150 μ L of above-mentioned several osmotic delivery system.The semipermeable plug ends of osmotic delivery system is placed the cuvette that is full of phosphate buffer (PBS), the flow modulator ends of osmotic delivery system is placed the cuvette that is full of moisture release medium.System is stored or insulation at 5 ℃ and 30 ℃ respectively.At specific time point, the solution that release medium can be removed and more renewed.Use reversed phase high-performance liquid chromatography (RP-HPLC) that the release medium of sampling is analyzed active agent content.The external accumulative total of IFN-ω that Fig. 4 was illustrated in June discharges.

The present invention can provide following advantage.Two-piece flow modulator makes the design of flow conditioner have motility and allows the manufacturability of flow conditioner.Shell and container are not whole, and make it possible to check before being inserted into flow conditioner in the container passage of flow conditioner.Two-piece flow modulator makes that the other mechanical force to passage minimizes in the process that flow conditioner is inserted in the container.Two-piece flow modulator allows to optimize by the passage on change inner core or the mobile insert motility of flow channel size in the shared trocar sheath of maintenance.

Although described embodiment with reference to limited embodiment, those skilled in the art should be appreciated that after understanding the present invention, can design other embodiment and do not break away from scope of the present invention disclosed herein.Therefore, scope of the present invention is only by the claim restriction of enclosing.

Claims (17)

1. be used for the implantable osmotic delivery system of active agent formulation, comprise:

The container of making by impermeable material;

First Room that comprises the osmotic engine material in container;

Second Room that comprises active agent formulation in container;

Be arranged in the container and the spacer that can move therein, described spacer limits first Room that comprises the osmotic engine material and second Room that comprises active agent formulation;

Be arranged on container first end, with the semipermeable plug of the first Room adjacency; With

Be arranged on container second end, with the flow conditioner of the second Room adjacency, described flow conditioner comprises:

Be positioned at the shell in the opening of second end of container of osmotic delivery system, described shell comprises inner surface;

Be inserted into the inner core in the described shell, described inner core comprises outer surface; With

The helical form flow channel that limits between the outer surface of the inner surface of described shell and inner core, described flow channel is suitable for the container delivery of active agent formulation from osmotic delivery system.

2. the implantable osmotic delivery system of claim 1, wherein flow channel is formed on the outer surface of the inner core that cooperates with the inner surface of shell.

3. the implantable osmotic delivery system of claim 1, wherein flow channel is formed on the inner surface of the shell that cooperates with the outer surface of inner core.

4. the implantable osmotic delivery system of claim 1 comprises the mobile insert that is arranged between shell and the inner core in addition, wherein forms flow channel in described mobile insert.

5. the implantable osmotic delivery system of claim 4, wherein shell, inner core and mobile insert are formed by inert material.

6. the implantable osmotic delivery system of claim 5, wherein inert material is nonmetallic materials.

7. the implantable osmotic delivery system of claim 1, wherein shell and inner core are formed by inert material.

8. the implantable osmotic delivery system of claim 7, wherein inert material is nonmetallic materials.

9. the implantable osmotic delivery system of claim 8, wherein said material is polyether-ether-ketone, polyaryletheretherketone, ultra-high molecular weight polyethylene, fluorizated ethylene-propylene, polymethylpentene or liquid crystal polymer.

10. the implantable osmotic delivery system of claim 1, wherein body seal meshes described inner core.

11. the implantable osmotic delivery system of claim 1, wherein said inner core comprise outside shoulder, described shell comprises inboard shoulder, and wherein said outside shoulder and the engagement of inboard shoulder are to prevent that in use inner core is discharged from shell.

12. the implantable osmotic delivery system of claim 1, wherein the length of flow channel is 10 to 50mm.

13. the implantable osmotic delivery system of claim 1, wherein the effective cross-section diameter of flow channel is 0.1 to 0.5mm.

14. the implantable osmotic delivery system of claim 1, wherein flow conditioner is press fit in second end of container.

15. each implantable osmotic delivery system of claim 1-14, wherein active agent formulation is selected from interferon-ω.

16. each implantable osmotic delivery system of claim 1-14, the material of wherein said container is selected from titanium or titanium alloy.

17. each implantable osmotic delivery system of claim 1-14, wherein said spacer is piston slidably.

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